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VATIS Update Biotechnology . Mar-Apr 2008

VATIS Update Biotechnology is published 4 times a year to keep the readers up to date of most of the relevant and latest technological developments and events in the field of Biotechnology. The Update is tailored to policy-makers, industries and technology transfer intermediaries.

IN THE NEWS

Indian biotech sector to generate US$5 billion by 2010

The Indian biotech industry will occupy 140 million square feet by 2010, says international real estate consultant Cushman & Wakefield in Bio Reality in India Report 2008. “Even though the country presently holds a minimal market share of 2 per cent of the global biotech market, it has immense potential to develop as a key player by 2010 and is expected to generate US$5 billion revenues, creating employment for a million by 2010 through its products as well as services,” the report says.

In addition to Bangalore, Hyderabad, Chennai, Pune and Mumbai, several tier II and tier III cities have emerged as the preferred destinations to set up a biotech facility. According to the report, Bangalore is estimated to witness approximately 6.5 million square feet demand from this sector alone during 2007-10. The city scored high on talent pool, government policy, investment environment and infrastructure. It has already witnessed the inflow of various biotech companies and research centres like Novo Nordisk, Syngene, Wipro Life Sciences, Aurigene and Novozymes.

Hyderabad is considered a pioneer in this sector due to government initiatives, sector-specific policies and an environment conducive to investment. The city has seen infrastructural development in the biotech domain wherein projects such as The Knowledge Park, The Biotech Park and Genome Valley have come up. Over 53 international biotech companies have established their operations in the Genome Valley over the last one year. The city will also have two biotech SEZs and three biotech parks in the next couple of years.

Chennai has experienced a new wave of growth. A world class laboratory infrastructure, TICEL Bio Park has been in operation since 2004. The city is set to have three more biotech parks and a biotech SEZ in the coming years. The government has planned a bioinformatics and a genomics centre that would leverage the pool of Indian bioinformatics scientists and low-cost software skills, facilitate research and enable entrepreneurs to commercialize their findings.

GM production growing in developing countries

Ninety per cent of farmers growing genetically modified (GM) crops are from developing countries, according to a report by the International Service for the Acquisition of Agri-Biotech Applications (ISAAA), a non-profit organization that promotes agricultural biotechnology for the poor. The report says that GM crops were grown by 11 million small and resource-poor farmers in 2007 – 90 per cent of the total number of GM-growing farmers worldwide. This is an increase of 18.3 per cent on 2006, when some 9.3 million small farmers were represented.

According to the report, 23 countries – 12 of which were developing nations – planted GM crops in 2007. In total, 114.3 million hectares of GM crops were cultivated worldwide, with 43 per cent of the global GM crop area in developing countries. In terms of area, the biggest GM producer is still the United States, followed by Argentina, Brazil, Canada, India and China. South Africa is the only African country to have authorized the sale of GM crops. Brazil saw the largest absolute increase (3.5 million hectares) in GM crop cultivation in 2007, with an estimated 15 million hectares of GM crops.

Friends of the Earth, the environmental organization, says GM crops are not alleviating hunger and poverty. The majority of GM crops are not aimed at the poor and are instead used for animal feed, biofuels and highly processed food products for consumption in rich countries. Their report also points out that GM crops designed to be herbicide tolerant have spawned herbicide-resistant weeds in the Argentina, Brazil and the United States, thereby needing greater use of chemicals to control them.

India becomes worldĂ˘â‚¬â„˘s second largest cotton producer

India is likely to grow genetically modified (GM) cotton on 80 per cent of its total cultivated area under the fibre in the next 2-3 years, a global research body said. The world’s second-biggest cotton producer, India hopes to produce a record output of 31 million bales (1 bale = 170 kg) in this crop year, as farmers plant more transgenic seeds. Indian farmers, who grow cotton on an average 9.06 million hectares, produced 28 million bales last year. “In 2007, Bt cotton area went up to 6.2 million hectares from 3.2 million hectares in 2006,” said Mr. Clive James, chairman of the International Service for the Acquisition of Agri-biotech Applications.

India allowed commercial cultivation of Bt cotton in 2002, leading to vehement protests from social activists who say GM crops are a health hazard, spoil soil texture and harm the environment. India will increasingly turn to laboratories to secure food supplies, as the country struggles to feed more than one billion people, say government officials. A fast-growing economy and increasing population have fuelled food consumption, while new industrial units and rapid migration to cities are turning farmland for other use.

“Self-sufficiency in food is crucial and the only way to ensure that is to adopt the GM technology. There cannot be two views on it,” said Dr. Mangla Rai, secretary of the government’s Department of Agriculture Research and Education. Last October, India approved the first large-scale field trials of a GM food crop, a new variety of the brinjal vegetable, which promises better yields with less use of pesticide.

China to set up biodiesel plant

China Agro-Technology (CAT) and the Beihai city government have signed a Memorandum of Understanding to set up a biodiesel refinery plant in Beihai, Guangxi Province. CAT expects to invest up to US$200 million over the next four years to operate the plant that, at full capacity, can produce 2 million tonnes of biodiesel per year. CAT has a target completion timeline for the factory of six months from the date of commencement.

Using present market prices, the net profit per tonne of oil would be US$350. CAT estimates that, beginning in the first quarter of 2009, it can produce a minimum of 80,000-100,000 tonnes, yielding a net profit of US$30-40 million, assuming current production capabilities. CAT founder and chairman, Dr. Harry He said, biodiesel has the highest demand of any commodity in China. China needs 12,400,000 tonnes of biodiesel to meet the requirements in 2008. However in 2007, the biodiesel supply in China was less than 1 million tonnes.

MARKET NEWS

Global stem cells market to reach new heights

Stem cell research has picked up pace like never before, and the global stem cells market is projected to reach about US$32.3 billion by 2012. The technology is leading to a new kind of cell-based medicine that is regenerative in nature, according to the report Stem Cell Research 2008 by Research and Markets. However, the report says, practicality and ethics dominate the ever controversial subject. Hence, it may take some more time, before a proper worldwide consensus emerges on the usage and procedures of stem cell research.

Stem cell research is most likely to gather pace in countries with less regulatory controls. Of all the countries, China has the most favourable environment for research, while the United Kingdom too has a strong research presence. The United States is the leader in stem cell research, but, the government controls the research grants though it places no restrictions on funds from private, state or local government resources, says the report.

Adult stem cells market is the largest tapped market while cord blood and embryonic stem cell markets, though with huge market potential, are still in infancy stages. The United States is the leader followed by the European and Asia-Pacific regions. With government regulations being amended in several countries, stem cell research is expected to pick up pace rapidly in the next few years. The potential of stem cell research – both medically and economically – is leading to huge investments by biotechnology companies, pharmaceutical companies and governments.

IBPL to market biotech products in Gulf region

Intas Biopharmaceuticals Ltd. (IBPL), India, has firmed up plans to supply and market its biotech products in the Gulf region. The Gulf Cooperation Council (GCC) region, which has a combined economy of US$715 billion and comprises Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates, offers unique business opportunities and benefits to IBPL. Initially, the company is looking to supply and market three products Neukine, Erykine and Intalfa.

Speaking on the development, Mr. Simon Daniel, chief executive (marketing) of IBPL, said, “The GCC region, which has significant requirement of products, and services in the biotech segment, is an important destination, keeping in view the market attractiveness for branded biologics, next only to the United States and European markets.”

Cognizant signs 5-year pact with AstraZeneca

Cognizant Technologies, IT and outsourcing services provider, has signed a five-year agreement with pharmaceutical company AstraZeneca to support its clinical data management services. The tie-up eyes US$95 million revenues, according to Cognizant. According to the agreement, Cognizant will provide centralized clinical data management services, including data management planning, clinical studies, medical coding, adverse event reconciliation and training for AstraZeneca’s global clinical development programmes. AstraZeneca will use the services to improve its R&D efficiency.

In 2004, AstraZeneca had roped in Cognizant for its businesses in North America, Europe and the Asia-Pacific. The healthcare and life sciences division of Cognizant has been finding a place in the Healthcare Informatics Top 100 list since the last three years. The division provides domain aligned consulting, business process and analytics solutions and employs over 10,000 professionals, including doctors, pharmacists, pharmacologists, biomedical engineers, biostatisticians, medical writers and GxP consultants.

Dow AgroSciences acquires Triumph Seed

Dow AgroSciences LLC, a wholly owned subsidiary of Dow Chemical Company, is expanding its plant biotechnology business with the acquisition of Triumph Seed of Texas, the United States. Triumph markets sunflowers, corn and sorghum in around 25 countries. It has been one of the industry leaders in sunflowers and was the first company in the industry to market worldwide the “short stature” sunflower hybrids. The agreement includes all commercial, production, research and development assets of the business.

“The Triumph acquisition is a great strategic fit for Dow AgroSciences. It strengthens our strong sunflower business by providing additional elite sunflower technology, a solid export business, and further expands our geographic corn and sorghum marketing areas in the United States,” said Mr. Stan Howell, vice president, North America, Dow AgroSciences. Dow AgroSciences will continue to market Triumph seed under the Triumph brand to complement its current Mycogen Seeds business.

Bharat Biotech to launch upgraded hepatitis B vaccine

Bharat Biotech International Ltd., India, is firming up plans to launch the thimerosal-free hepatitis B vaccine in the global markets. Thimerosal-free implies that the vaccine is free of chemicals and does not need preservatives. Bharat Biotech is the first Indian vaccine manufacturer to successfully produce Revac-Bmcf, and introduce it to the domestic market. A thimerosal-free hepatitis B vaccine, which is an upgraded version, could emerge as a preferred choice for paediatricians, especially for administering it to a new-born, within 12 hours of delivery. The company has effectively optimized its production technologies to ensure the phasing out of thimerosal, as a preservative wherever possible. It has a current portfolio of 10 injectable sterile preparations, including seven vaccines.

AVI BioPharmaÂ acquires Ercole Biotech

AVI BioPharma Inc. and Ercole Biotech Inc. have announced the execution of a definitive merger agreement pursuant to which AVI will acquire Ercole, a pioneer in developing drugs to directed alternative RNA splicing. AVI and Ercole have collaborated since December 2006 to develop drug candidates. Under the terms of the agreement, AVI will issue up to US$7.5 million in AVI common stock valued at US$1.3161 per share in exchange for all outstanding shares of Ercole stock not already owned by AVI. In addition, AVI will assume responsibility for up to US$1.5 million in liabilities of Ercole, to be paid by a combination of cash and AVI stock. Liabilities exceeding US$ 1.5 million will be deducted from the US$7.5 million in common stock. The transaction is expected to close by 21 March.

“The acquisition of Ercole is a major step toward AVI’s goal of becoming the pre-eminent developer of drugs that modify RNA splicing,” said Dr. Leslie Hudson, CEO of AVI. “This therapeutic approach takes advantage of a fundamentally important mechanism – alternative RNA splicing – for therapeutic intervention. We believe this intervention can correct genetic mutations in situ or produce clinically desirable variants of relevant therapeutic proteins in vivo. Our acquisition of Ercole brings us significant scientific expertise and fundamental patents to help us reach this goal.”

Nicholas Piramal renamed as Piramal Healthcare

Nicholas Piramal India Ltd., the two-decade old pharmaceutical company has a new corporate identity. The pharmaceutical producer will have the new name of Piramal Healthcare Ltd., subject to the approval of shareholders and statutory authorities. NPIL Research & Development Ltd. was recently renamed Piramal Life Sciences Ltd., and other portfolio companies of the Ashok Piramal group are also being rebranded. NPIL Laboratories and Diagnostics Pvt. Ltd. will be known as Piramal Diagnostic Services Pvt. Ltd. and Gujarat Glass Ltd. will be Piramal Glass Ltd.

It is expected that the name change would help the group create a unified umbrella branding for all its commercial enterprises. The Piramal Group believes this exercise is would develop a value-driven identity that unifies the diverse companies within the Group. It says the move was based on the results of an analysis within the group spread over the past two years that revealed an affinity with three values that the Group has now adopted – knowledge, action and care.

GENOMICS

Genes that protect against atherosclerosis

One way of combating atherosclerosis is to reduce levels of bad LDL cholesterol in the blood. Scientists at the Swedish medical university Karolinska Institutet have now identified the genes that bring about this beneficial effect. In a new study on mice, the research group has shown that the accumulation of plaque that causes myocardial infarction and stroke can be prevented if levels of the LDL cholesterol are reduced before atherosclerotic plaque has progressed beyond a particular point. The group has also identified a network of 37 genes that lowers levels of blood cholesterol and brings about the beneficial effect.

“Previously, much atherosclerosis research was focused on identifying ways to stabilize the most dangerous plaques in order to prevent them rupturing and causing myocardial infarction or stroke,” says Dr. Johan Björkegren, who led the study. The discovery allows researchers to target the actual development of dangerous plaques. Rather than covering individual vessel wall genes, their discovery encompasses a network of genes, and one that explains their mutual interaction. “We now have enough tools and knowledge of system biology to take on the total complexity of these diseases,” says Dr. Johan Björkegren.

Monkey gene that blocks AIDS viruses is more evolved

Researchers at Harvard Medical School, the United States, have identified a gene in Asian monkeys that may have evolved as a defence against lentiviruses, the group of viruses that includes HIV. The study suggests that AIDS is not a new epidemic. The gene, called TRIM5-CypA, is a hybrid of two cellular genes TRIM5 and CypA. The combination produces a single protein capable of blocking infection by viruses closely related to HIV. This is the second time researchers have identified a TRIM5-CypA gene in monkeys. The other hybrid gene, called TRIMCyp, was discovered in 2004 in South American owl monkeys.

Normally, it is assumed that similar DNA sequences, present in the same location in the genomes of two or more species, evolved only once. The gene arises first in a common ancestor and is subsequently inherited by all the species that descend from that ancestor. In the case of TRIM5-CypA and TRIMCyp, this does not appear to be the case. TRIM5-CypA was not found in monkeys closely related to the Asian macaques. Likewise, owl monkey TRIMCyp was not found in any other species of South American primate. Researchers interpret this to mean that the two genes arose independently, once in owl monkeys and once in macaques. More tellingly, although the protein sequences specified by the two TRIM5-CypA genes are similar, at the DNA level it is obvious that the molecular events leading to formation of the two genes were different.

Evolutionary biologists refer to the acquisition of a similar adaptation in different species as “convergent evolution”, an example being the independent appearance of flight in both birds and bats. The Harvard team’s genetic evidence shows that the two TRIM5-CypA genes constitute a clear and particularly striking example of convergent evolution. Moreover, the kinds of molecular events required to construct the two TRIM5-CypA genes are thought to be rare. That the process occurred at least twice during primate evolution suggests that the combination of the TRIM5 and CypA genes provided a strong evolutionary advantage to the individuals in which they originally appeared. An intriguing possibility is that the newly formed genes prevented infection by prehistoric viruses related to modern AIDS viruses. If so, this could mean that AIDS-like epidemics are not unique to our time.

New stem cell technique improves genetic alteration

University of California Irvine (UCI) researchers have discovered a vastly improved method for genetically manipulating human embryonic stem cells (hESC), making it easier for scientists to study and potentially treat thousands of disorders. The technique blends two cell-handling methods in use to improve cell survival rates and increase the efficiency of inserting DNA into cells. It is up to 100 times more efficient than current methods at producing hESC with desired genetic alterations.

“The ability to generate large quantities of cells with altered genes opens the door to new research into many devastating disorders,” said Dr. Peter Donovan, professor of biological chemistry and developmental and cell biology at UCI. “Not only will it allow us to study diseases more in-depth, it also could be a key step in the successful development of future stem cell therapies.”

Dr. Donovan, together with Dr. Leslie Lock and Dr. Kristi Hohenstein, used growth factors – proteins that help keep cells alive – to keep cells alive, and then used a technique called nucleofection to insert DNA into the cells. Nucleofection employs electrical pulses to punch tiny holes in the outer layer of a cell through which DNA can enter the cell. With this technique, scientists can introduce into cells DNA that makes proteins that glow green under a special light. For every one genetically altered cell generated using the chemical method, the new growth factor/nucleofection method produces between 10 and 100 successfully modified cells, UCI scientists estimate.

Scientists can use the new technique to develop populations of cells with abnormalities that lead to disease. They can then study those cells to learn more about the disorder and how it is caused. Scientists also possibly could use the technique to correct the disorder in stem cells, and then use the healthy cells in a treatment. The method could help treat monogenic diseases, which result from modifications in a single gene occurring in all cells of the body.

Genetic markers found for recurring lung cancers

Researchers at the Johns Hopkins Kimmel Cancer Centre, the United States, have uncovered clearly recognizable genetic alterations in tumours and tissue removed from patients with early-stage lung cancers that look like good predictors of which of these cancers are more likely to recur. The discovery could change the approach to treating even the smallest lung cancers, which are known to recur within five years in 30-40 per cent of patients. “This is DNA forensics for cancer,” says Dr. Malcolm Brock. “While there may be no trace of cancer that we can spot after surgery with a microscope, the DNA evidence from these tumours may have been left at the scene.”

The particular molecular flags the team identified are chemicals known as methyl groups that latch on to the DNA ladder structure of a gene. Methylation is a commonly known phenomenon in the formation and development of cancers because they serve as signals to cells to switch certain genes on or off. Disruption in these signals may create a cascade of abnormal proteins that lead to cancer or its recurrence.

Dr. Brock and his team combed through more than 700 surgical samples from 167 early stage, non-small cell lung cancer patients searching for specific methylation patterns. Tumour and lymph node tissues from 51 patients whose cancers recurred within 40 months were compared with samples from the remaining 116 patients whose cancers did not recur. The scientists tested all the samples for methylation on seven genes linked to lung cancer. Four of them – p16, H-cadherin, APC and RASSF1A – showed the highest amounts of methylation in patients whose cancers recurred. For many of the genes, the study revealed a two-fold difference in methyl marks between recurrent cancers and those that did not return.

Brock and his colleagues also found that cancers returned even more swiftly than average for 11 patients who had higher than normal methylation in a deadly combination of p16 and H-cadherin genes located in both tumour tissue and a lymph node distant from the original tumour area. Eight of the 11 patients with this methylation pattern had cancers that returned within a year. By 30 months, the remaining three patients’ cancer had also recurred.

Role of tiny RNAs in controlling stem cell fate

In the United States, scientists at the Gladstone Institute of Cardiovascular Disease (GICD) and the University of California San Francisco have identified how tiny genetic factors called microRNAs may influence the differentiation of pluripotent embryonic stem (ES) cells into cardiac muscle. Scientists in the lab of GICD Director, Dr. Deepak Srivastava showed that miR-133 and miR-1, two microRNAs associated with muscle development, encourage heart muscle formation and actively suppress genes that could turn the ES cells into undesired cells like neurons or bone.

More than 450 human miRNAs have been described and each is predicted to regulate numerous proteins that may determine cellular differentiation. While many ES cell-specific miRNAs have been identified, the role of individual miRNAs in ES cell differentiation had not been determined. The researchers have now shown that miRNAs can control how pluripotent stem cells determine cell lineage, in this case, as cardiac muscle cells.

They found miR-1 and miR-133 to be active at the early stages of heart cell formation, when an ES cell is first “deciding” to become mesoderm, one of the three basic tissue layers in mammals and other organisms. Activity of either in ES cells cause genes that encourage mesoderm formation to be turned on. Equally important, they caused other genes that would have told the cell to become ectoderm or endoderm to turn off.

Genes that may delay old age

Dr. Brian Kennedy at the University of Washington in Seattle, the United States, and his team have discovered more than a dozen genes that play a crucial role in the ageing process, raising hopes of treatments to delay old age. By piecing together how different genes contribute to ageing, researchers expect to find ways to slow the process and treat diseases associated with old age.

The researchers looked for genes that control the ageing process in two primitive organisms, yeast cells and nematode worms. The two organisms are separated by 1.5 billion years of evolution, so any genes they have in common are likely to be crucial to life and may even have similar versions in humans. The scientists found that of the 276 genes known to affect ageing in nematode worms, only 25 were also present in yeast. At least 15 of these have similar versions in humans. Many of these genes were linked to chemical signals triggered by food. Previous studies have shown that drastic calorie reduction in an organism’s diet can prolong its life span, though often at the expense of fertility. If scientists can find out how age-related genes are affected by an extremely low-calorie diet, they may be able to “mimic the effects of dietary restriction with a drug,” said Dr. Matt Kaeberlein, a member of the research team.

MEDICAL BIOTECH

Groundbreaking alternative to stem cell therapy

Blasticon Biotechnologische Forschung GmbH, Germany, has made a breakthrough in cell biology: it has patented a technique by which monocytes (mature white blood cells) obtained from vein can be turned into cells with programmable properties comparable to those of stem cells, and differentiated into different functional cells. According to Dr. Fred Fandrich, director of general surgery and thoracic surgery at the Schleswig-Holstein University Clinic and founder of Blasticon, they can “reprogramme these programmable cells into the desired target cells, for example liver or muscle cells or cells in pancreatic islets of Langerhans.”

The therapeutic possibilities of the technique lie in replacing defective or missing cells (regenerative medicine) or producing cells that regulate the immune system – a significant advancement in the treatment of autoimmune diseases or for transplant medicine. The “reprogrammed” cells can be used both as diagnostic agents and for therapeutic purposes. Inflammatory bowel diseases, diabetes, rheumatism, cardiac infarction, liver diseases, and kidney and liver transplants are among the main therapeutic areas. The reprogrammed cells make it possible to attack illnesses at their origin and to shorten duration of treatment.

AlzheimerĂ˘â‚¬â„˘s disease has genetic leanings

If both parents have Alzheimer’s disease, then the offspring is much more likely than other people to get it too, say researchers at the University of Washington in Seattle, the United States. The study focused on 111 families in which both parents were diagnosed with Alzheimer’s disease, the most common form of dementia among the elderly, and assessed the risk for developing it among the offspring. Together, the parents had 297 children who lived into adulthood. Of the 98 men and women who were at least 70 years old, 41 – about 42 per cent – developed Alzheimer’s disease.

In the general population, risk for the disease begins to rise at about age 65, with the number of people developing the disease doubling every five years beyond that, experts say. But about two-thirds of the adult offspring in the study still had not reached age 70. Counting all 297 of these adult offspring regardless of age, 23 per cent had already been diagnosed with Alzheimer’s disease. That compares with the about 10 per cent chance that an average person will develop the disease, says Dr. Thomas Bird, one of the researchers. “I think it confirms that there is a strong genetic component in the disease and that is not a surprise,” said Dr. Bird.

Protein in embryonic stem cells control malignant tumour

A protein that governs development of human embryonic stem cells (hESCs) also inhibits the growth and spread of malignant melanoma, the deadliest skin cancer, research at Northwestern University, the United States, has discovered. The Northwestern scientists, led by Dr. Mary J. C. Hendrix, also found that the protein, called Lefty, prevents aggressive breast cancer cells from metastasizing. Importantly, Lefty is secreted only in hESCs, and not in any other stem cell type tested – including stem cells isolated from amniotic fluid, cord blood or adult bone marrow – or placental cells. As hESCs are pluripotent, they can become any of the 200-plus cell types in the adult body, depending on the signals they receive from their micro-environment. Malignant cancer cells also receive signals from micro-environment to promote tumour growth and metastasis.

Dr. Hendrix and co-researchers had previously shown that a three-dimensional matrix conditioned by hESCs induced metastatic melanoma cells to revert to a normal, skin cell-like type with the ability to form colonies in the manner of hESCs. In later experiments, they found that aggressive melanoma and breast cancer produce a morphogenic protein called Nodal, which is essential for hESC’s pluripotency. The current study reports that the Lefty protein inhibits production of Nodal and therefore plays a major role in embryonic cell differentiation and development.

The researchers found that metastatic tumour cells do not express Lefty, allowing them to over produce Nodal in an unregulated manner. However, when they exposed metastatic tumour cells to the micro-environment of hESCs containing Lefty, they witnessed dramatically reduced Nodal expression in these cancer cells together with decreased tumour cell growth and invasiveness and an increase in apoptosis, or programmed cell suicide. However, while findings from the study suggest that hESC-derived Lefty may have the potential to prevent metastasis, it is not the only tumour suppressive factor within the embryonic microenvironment.

Cause of influenza epidemics uncovered

The exchange of genetic material between two closely related strains of the influenza A virus may have caused the 1947 and 1951 human flu epidemics, according to biologists. The findings by a group of researchers drawn from different institutions in the United Sates could help explain why some strains cause major pandemics and others lead to seasonal epidemics.

Until now, it was believed that severe pandemics are caused by re-assortment – human influenza viruses swapping genes with influenza viruses that infect birds – while regular influenza epidemics are triggered by viral mutation. But it has been a mystery why there are sometimes very severe epidemics – like the ones in 1947 and 1951 – that look and act like pandemics, even though no human-bird viral re-assortment event occurred. There was a total vaccine failure in 1947, as the virus had undergone a tremendous evolutionary change. The research team thinks that the 1947 virus did not just mutate, but that a re-assortment involving two human viruses made this unusual virus.

The researchers analysed the evolutionary patterns in the H1N1 strain of the influenza A viruses by looking at 71 whole-genome sequences sampled between 1918 and 2006 and representing 17 different countries on five continents. Making use of the genome data, they constructed phylogenetic trees that represent evolutionary relationships across all eight genome segments of the virus. Large differences in the shapes of these eight trees signified that re-assortment events had occurred.

Currently, there are many types of influenza virus that circulate only in birds, which are natural viral reservoirs. Although the viruses do not seem to cause severe disease symptoms in birds, so far three of these viral types have infected humans – H1N1, H2N2, and H3N2. The study shows that the evolution of a virus is not limited to the mutation of single lineage, and that there are multiple strains co-circulating and swapping genetic material. The H1N1 and H3N2 strains, for instance, are occasionally generating hybrid H1N2 viruses.

Potential drug target for AlzheimerĂ˘â‚¬â„˘s disease identified

Research at the University of California San Diego (UCSD), the United States, has demonstrated in mice a way to reduce the overproduction of a peptide associated with Alzheimer’s disease. The study, which showed substantial improvement in memory in an animal model of Alzheimer’s disease, was led by Dr. Vivian Y. H. Hook, professor of neurosciences, pharmacology and medicine at the UCSD School of Medicine.

A hallmark of Alzheimer’s disease is the deposits of amyloid plaque in the patient’s brain. Amyloid plaque is composed primarily of the neurotoxic beta-amyloid (Aâ) peptide, which is believed to be a major factor that causes the disease. The Aâ peptides are “cut” out from a larger protein called the amyloid precursor protein (APP) and bind together to form plaques in brain regions responsible for memory. One drug strategy to fight Alzheimer’s disease is to reduce Aâ production. “We discovered two chemical compounds that inhibit a new enzyme target, leading to reduced production of beta-amyloid and improved memory in a mouse model of Alzheimer’s disease,” said Dr. Hook.

To generate Aß, the protease enzymes must cut the APP amino acid sequence in two places: at the beta-secretase and the gamma-secretase sites. By inhibiting proteases and thus preventing the enzymatic “cutting” of the APP chain into smaller peptides, the research team observed improved memory, as well as reduced levels of Aß protein in the brain of mice bred to exhibit Alzheimer’s disease symptoms. Dr. Hook’s team found that a protease, called Cathepsin B (CatB), works to cut the normal beta-secretase site – which is the site present in more than 99 per cent of patients with Alzheimer’s disease. They also tested compounds that inhibit CatB – E64d and CA074Me – in a mouse model of Alzheimer’s disease with the normal beta-secretase site.

Dr. Hook said that a drug that duplicates this reduction by targeting CatB in humans could be an effective treatment for Alzheimer’s disease in the more than 99 per cent of individuals with the normal beta-secretase site. “By disabling the enzyme’s ability to cut the ‘beta’ end of the amino acid sequence, researchers may discover a way to limit production of neurotoxic Aâ and reduce amyloid plaques in the brain,” she said.

Human umbilical cord blood for rejuvenating aged brain

When researchers at University of South Florida, the United States, injected human umbilical cord blood cells (UCBC) into aged laboratory animals, they found improvements in the micro-environment of the hippocampus region of the animals’ brains and a subsequent rejuvenation of neural stem/progenitor cells. The research presents the possibility of a cell therapy aimed at rejuvenating the aged brain.

According to Dr. Alison Willing, “Brain cell neurogenesis decreases dramatically with increasing age, mostly because of a growing impoverishment in the brain’s micro-environment.” She said “The increase in neurogenesis we saw after injecting UCBCs seemed to be due to a decrease in inflammation.” The lead author Dr. Carmelina Gemma said that the decrease in neurogenesis that accompanies aging is a result of the decrease in proliferation of stem cells, not the loss of cells. The study found that the number of proliferative cells increased within 24 hours following the UCBC injections into the aged laboratory rats and that the increased cell proliferation continued for at least 15 days following a single treatment. “We think that UCBCs may have a similar potential to reduce inflammation and to restore some of the lost capacity of stem/progenitor cells to proliferate and differentiate into neurons,” said Dr. Paula C. Bickford, who led the research team.

PROTEOMICS

Key target protein found for new pneumonia vaccine

A protein may hold the key to a new vaccine that can effectively target pneumonia, according to researchers at the Children’s Hospital of University of Pittsburgh Medical Centre. Dr. Jay K. Kolls of the Division of Pediatric Pulmonary Medicine, Allergy and Immunology, identified the importance of the protein interleukin 22 (IL-22) in the immune response to a strain of bacterial pneumonia. In the laboratory, the researchers were able to effectively treat mice with pneumonia by using purified IL-22. “Currently there is no vaccine that covers all kinds of pneumonia and antibiotic treatment is sometimes limited by antibiotic resistance,” says Dr. Kolls. “Our results raise the possibility of developing new protein-based therapies using IL-22 to limit or prevent pneumonia.”

Protein that regulates the human genome

Molecular biologists at Cornell University in the United States have discovered how a protein called PARP-1 binds to genes and regulates their expression across the human genome. Knowing where PARP-1 is located and how it works may allow scientists to target this protein while battling common human diseases. PARP-1 and another genome-binding protein called histone H1 compete for binding to gene “promoters” (the on-off switches for genes) and, as such, act as part of a control panel for the human genome, explains Dr. W. Lee Kraus, associate professor in molecular biology. H1 puts genes in an “off” position and PARP-1 turns them “on”. The new study shows that for a surprising number of genes, the PARP-1 protein is present and histone H1 is not, helping to keep those genes turned on.

The human cells act when they are exposed to physiological signals, such as hormones, or to stress signals, such as metabolic shock or DNA damage caused by agents like ultraviolet light. One of the cellular responses is the production of nicotinamide adenine dinucleotide (NAD), a metabolic communication signal. NAD promotes the removal of PARP from the genome and alters PARP-1’s ability to keep genes on. Knowing where the PARP-1 protein is located helps scientists to better understand the effects of synthetic chemical inhibitors of PARP-1 activity, which are being explored for the treatment of human diseases such as stroke, heart disease and cancer.

Structure of a protein that mutates DNA of HIV-1 revealed

Understanding the structure of proteins involved in inhibiting HIV-1 infection could help in the battle against AIDS, and researchers at the University of Minnesota have taken a crucial step in that direction. Dr. Hiroshi Matsuo and Dr. Reuben Harris – assistant professors in the Department of Biochemistry, Molecular Biology and Biophysics – have determined the structure of APOBEC3G, a protein that inhibits HIV-1. This discovery is the first to shed light on the protein’s atomic structure.

The APOBEC3G is capable of modifying HIV DNA so that the virus is no longer infectious. HIV-1, however, has developed a way to evade this cellular protein with its own protein called Vif, which literally triggers the destruction of APOBEC3G. The discovery will help develop methods to neutralize Vif before it has a chance to destroy the APOBEC3G.

Protein target for diabetes drug regulates blood pressure

University of Iowa researchers have identified a molecular pathway in blood vessels that controls blood pressure and vascular function and may help explain why certain drugs for type II diabetes also appear to lower patients’ blood pressure. The focus of the study is a protein called peroxisome proliferator-activated receptor gamma (PPAR gamma), which plays a critical role in fat metabolism and insulin action, and appears to link metabolic disorders, like type II diabetes, with cardiovascular disease.

Thiazolidinediones (TDZs) drugs, which are used to treat type II diabetes, target and activate PPAR gamma. In addition to controlling blood sugar, these drugs also appear to lower blood pressure. TZDs, however, have some serious side-effects, such as weight gain and water retention. A recent study suggested that one TZD might increase the incidence of fatal and non-fatal heart attacks in diabetes patients.

Researchers led by Dr. Curt Sigmund, professor of internal medicine and molecular physiology and biophysics, tested the idea that these two beneficial effects of TZDs are produced through two separate PPAR gamma pathways. Working with mice, the team knocked out the function of PPAR gamma in vascular smooth muscle, which surrounds blood vessels. The mice developed high blood pressure and severe vascular dysfunction, which resembled the vascular disorders often seen in patients with advanced type II diabetes.

PPAR gamma is a transcription factor and when it is activated, a cascade of signals is initiated, which controls gene expression – some genes are turned on and others are turned off. In particular, inflammatory genes are turned off and antioxidant genes turned on. Having identified the PPAR gamma pathway, the next question for the scientists is which genes are being turned on or off to produce the antihypertensive effect.

Molecular biologists at the University of California San Diego (UCSD), the United States, have found one piece of the complex puzzle of autophagy, or “self-eating”, performed by all eukaryotic cells to keep themselves healthy. The finding is important as it allows scientists to control this one aspect of cellular autophagy, and may lead to the ability to control other selective autophagy. This, in turn, could help illuminate autophagy’s role in aging, immunity, neurodegeneration and cancer.

Led by Dr. Suresh Subramani, a biology professor, the UCSD researchers identified a novel protein called Atg30 – one of 31 required for autophagy-related processes – from Pichia pastoris yeast. Atg30 controls the degradation of peroxisomes, a sub-compartment of cells that generate and dispose of harmful peroxides – the by-products of oxidative chemical reactions. The team is working to understand how and why peroxisomes are selected by the lysosome for degradation.

What the biologists found, is that the new protein can “mediate peroxisome selection during pexophagy – that is, it is necessary for pexophagy, but not for other autophagy-related processes,” says Dr. Jean-Claude Farré, the biologist who identified Atg30. The team has established that Atg30 is a “key player” in the selection of peroxisomes for delivery to “the autophagy machinery” for re-cycling. “For the first time, we can use a protein to control the process,” Dr. Subramani said. “It is an important step in understanding the workings of cells.”

AGRI BIOTECH

Draft sequence of maize genome unveiled

A team of scientists led by Washington University, St. Louis, has unveiled a working draft of the maize (corn) genome. “This first draft of the genome sequence is exciting because it is the first comprehensive glimpse at the blueprint for the corn plant,” said Dr. Richard K. Wilson, the project’s leader. The US$29.5 million project was initiated in 2005 and is jointly funded by the National Science Foundation, the United States Department of Agriculture and the United States Department of Energy. Maize is only the second crop after rice to have its genome sequenced.

The team working on the endeavour – including scientists at the University of Arizona, Cold Spring Harbour Laboratory and Iowa State University – has already made the sequencing information accessible to scientists worldwide by depositing it in GenBank, an online public DNA database. The draft covers about 95 per cent of the corn genome, and scientists will spend the remaining year of the grant finalizing the sequence. The group sequenced a corn variety known as B73, developed at Iowa State decades ago. The genetic code of corn consists of 2 billion bases of DNA. By comparison, the rice genome is far smaller, containing about 430 million bases.

Scientists unravel the genetic coding of the pea

The pea (Pisum sativum) is one of many important crop species that is unsuited to the commonly used genetic crop modification techniques based on Agrobacterium. Researchers from the INRA Plant Genomics Research Unit and the INRA Grain Legumes Research Unit, both in France, have now discovered the first high-throughput forward and reverse genetics tool for the pea, which could have major benefits for crop breeders.

Researchers led by Dr. Abdelhafid Bendahmane developed a high-quality genetic reference collection of P. sativum mutants under the European Grain Legumes Integrated Project. They used plants from an early-flowering garden pea cultivar, Caméor, to create a mutant population, which they then systematically phenotyped for use in both forward and reverse genetics studies. The team established a pea Targeting Induced Local Lesions IN Genomes (TILLING) platform with DNA samples from 4,704 plants. TILLING is an alternative to Agrobacterium-based techniques, and uses ethane methyl sulphonate mutagenesis together with a gene-specific detection of single-nucleotide mutations. This reverse genetic strategy can be applied to all types of organisms and can be automated for high-throughput approaches.

Following this study, the researchers created a database called UTILLdb, which describes each mutant plant at different developmental stages (from seedling through to fruit maturation), and also incorporates digital images of the plants. UTILLdb contains phenotypic and sequence information on mutant genes, and can be searched for TILLING alleles of genes of interest, using the ‘BLAST’ tool, and for plant traits of interest, using keyword searches.

Insecticide combo delivers knockout punch

A cocktail containing a plant protein and a common insecticide may be more lethal to crop pests than either ingredient used alone, according to a team of biologists in the United States. The one-two punch also inhibits the insects’ growth rate and reduces their chance of developing resistance. “We found a synergistic effect, where the two insecticides together decreased the growth rate of caterpillars more than either one did alone,” said Dr. Dawn Luthe, professor of plant stress biology at Penn State University (PSU).

Dr. Luthe, and co-researchers from Mississippi State University and the Department of Agriculture studied a unique insecticide, known as Mir1-CP, developed from certain maize strains from Antigua. Their goal was to see if Mir1-CP, when used in tandem with other biological pesticides, such as the Bt toxin, can prevent pests from developing resistance and make the toxin more effective. Unlike Bt, Mir1-CP breaks down proteins in a protective membrane covering the mid-gut. This membrane acts as a barrier that protects the caterpillar from toxins in the diet, and cycles nutrients to the mid-gut.

“It is the caterpillar’s first line of defence against toxins and chemicals in its diet,” said Dr. Luthe. The researchers fed insects a sub-lethal dose of Bt toxin and Mit1-CP to test their effectiveness on the pests. They found that when used alone, a concentration of Bt at five parts per billion killed four per cent of all maize earworms and five per cent of tobacco budworms. Mir1-CP, when used at a concentration of 60 parts per billion, killed eight per cent of the maize earworms and three per cent of the tobacco budworms. But when researchers added the two insecticides together, the mixture killed 61 per cent of maize earworms and 57 per cent of tobacco budworms – more than 10 times better than either by itself. The study indicated a significant decrease in the growth rate of the survivors. “We think that Mir1-CP is making holes in the membrane, which in turn is making it easier for the Bt toxins to reach the insects’ mid-gut,” said Dr. Luthe. The researchers suggest strains of corn that naturally produce Mir1-Cp could be cross-bred with other strains of corn that produce Bt to develop new varieties that are more effective against pests.

Gene involved in carbon dioxide uptake in plants

Research groups of the Department of Biological and Environmental Sciences of the University of Helsinki, Finland, and the University of California San Diego (UCSD), the United States, have found a gene that is centrally involved in the regulation of carbon dioxide uptake for photosynthesis and water evaporation in plants. The discovery can aid the development of drought-tolerant crops.

Stomata are tiny pores on the plant leaf surface, through which the leaves absorb carbon dioxide necessary for photosynthesis and release moisture into the air. The plasma membranes of the guard cells that surround the stomatal pore contain several types of ion channels, which control the opening and closing of the circular guard cells when the plant encounters a stressful situation such as drought. One anion channel, which is of central importance in the regulation of stomatal activity, was identified only recently by scientists.

Professor Jaakko Kangasjärvi and his research group from the University of Helsinki identified the anion channel using a mutation of Arabidopsis thaliana. The mutant does not react by closing its stomata as a response to high ozone or carbon dioxide concentration in the air like a healthy plant does. UCSD scientists showed using electrophysiological measurements that the identified gene – named “slow anion channel 1 (SLAC1) – encodes an anion channel involved in the regulation of all the main stomatal activities. When developing drought-resistant crops, it is important to know well the mechanisms that regulate stomata, through which plants evaporate moisture.

A gene that elongates the shape of tomatoes

Crop scientists have cloned a gene that controls the shape of tomatoes, a discovery that could help unravel the mystery behind the huge morphological differences among edible fruits and vegetables, as well as provide new insight into mechanisms of plant development. The gene, dubbed SUN, is only the second ever found to play a significant role in the elongated shape of various tomato varieties, said Dr. Esther van der Knaap, assistant professor of horticulture and crop science at OSU Ohio Agricultural Research and Development Centre, the United States.

“We are trying to understand what kind of genes caused the enormous increase in fruit size and variation in fruit shape as tomatoes were domesticated,” said Dr. van der Knaap. Through genetic analysis, the researchers narrowed down the region of the genome that controls the elongated fruit shape, and eventually narrowed down that region to a smaller section that could be sequenced to identify the genes present at that location. Dr. van der Knaap’s team thus found the gene SUN, which takes its name from the “Sun 1642” cultivated variety where it was found – an oval-shaped, Roma-type tomato with a pointy end. The gene was also found in elongated varieties, such as the “Howard German” tomato.

To determine whether this gene is actually responsible for causing changes in fruit shape, the researchers conducted many plant-transformation experiments. When the SUN gene was introduced into wild, round fruit-bearing tomato plants, they ended up producing extremely elongated fruit. And when the gene was “knocked out” of elongated fruit-bearing plants, they produced round fruit similar to the wild tomatoes. Something else the researchers found out is that SUN encodes a member of the IQ67 domain of plant proteins, called IQD12, which they determined could make tomatoes elongated instead of round.

IQD12 is only the second IQ67 protein-containing domain whose function in plants has been identified. The other one, AtIQD1, was discovered in Arabidopsis thaliana, in which it increases levels of glucosinolate. While SUN doesn’t seem to be affecting glucosinolate levels in tomato, there appears to be a common link between the two genes, which is that they may be regulating tryptophan levels in the plant, says Dr. van der Knaap.

Major leap in biofuel technology

At the University of Maryland, the United States, research that started with bacteria from the Chesapeake Bay has led to a process that may be able to convert large volumes of all kinds of plant products, from leftover brewer’s mash to paper trash, into ethanol and other biofuel alternatives to gasoline. That process, developed by Dr. Steve Hutcheson and Dr. Ron Weiner, professors of cell biology and molecular genetics, is the foundation of their incubator company Zymetis.

The Zymetis process can make ethanol and other biofuels from many different types of plants and plant waste called cellulosic sources. Cellulosic biofuels can be made from non-grain plant sources such as wastepaper, brewing by-products, agricultural residues, as well as energy crops like switchgrass. The secret of the process is a marsh grass bacterium, Saccharophagus degradans. The bacterium has an enzyme that could quickly break down plant materials into sugar.

The Zymetis researchers were unable to isolate the bacterium in nature, but they discovered how to synthesize the enzyme. The result is Ethazyme, which degrades the tough cell walls of cellulosic materials and convert the plant material into bio-fuel ready sugars in one step, at a significantly lower cost and with fewer caustic chemicals than current methods.

MARKET NEWS

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